The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. However, ARV programs have encountered many challenges, some of which are similar to those observed in North America and some of which differ, including the availability of ARV regimens, widespread use of nevirapine for prevention of mother-to-child HIV transmission, and the presence of non-B HIV subtypes. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring and potential delays in detecting virologic failure on genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression. We are currently evaluating the impact of ARVs on HIV incidence among HIV discordant couples. 250 HIV-1 discordant couples were followed between 2004-2009. During this period 32 HIV-1-positive partners were initiated on ARVs since they met immunologic criteria for initiation of therapy. 42 HIV-1 transmissions occurred prior to ARV initiation with an incidence of 9.2/100 pys. In the 32 couples in which HIV-1 index partners started ARVs, no HIV-1 transmissions occurred while on ARVs. We continue to scale up treatment of discordant couples and have yet to document any transmissions among couples who have started ART. Data from this study as well as others demonstrate that antiretroviral therapy reduces the risk of HIV transmission among HIV-1 discordant couples. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We analyzed antiretroviral drug susceptibility in HIV from 38 participants failing first and second line antiretroviral treatment (ART) regimens in Rakai, Uganda. At baseline, four (13%) of 31 participants had mutations associated with resistance to either nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs or NNRTIs). Most participants failing first-line ART had mutations to NNRTIs (86%) and lamivudine (81%), but only 22% had other NRTI mutations. None of the six participants failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only. We compared the genotypic resistance patterns between patients with VLM to those with IM in Kampala, Uganda. Between 2004-2008, 559 antiretroviral nave clients were enrolled in a prospective cohort, initiated ART, and monitored with viral load and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months and immunologically monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Virologic failure rates at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and 10% in the IM group at 36-40 months. 59% patients in the VLM group compared to 90% in the IM group, (P<0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. Routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. Attempts to develop clinical and laboratory algorithms in Uganda to target viral load testing have unfortunately failed to improve on the current WHO criteria, making a simple and affordable viral load test a public health priority for sub-Saharan Africa. We have continued to examine the etiology of severe sepsis in Ugandan hospitals and evaluate interventions to improve mortality outcomes. We previously showed that hypoglycemia was a significant predictor of in hospital mortality among patients admitted with severe sepsis. A follow-up intervention study evaluated the impact of early fluid resuscitation and intensive monitoring among 426 Ugandan patients presenting with severe sepsis. This simple, early intervention lowered the risk of mortality by 26% compared to standard of care management. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. Daily suppression of HSV-2 reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. We enrolled 440 HIV-1, HSV-2 dually infected adults with CD4+ T-cell counts 300-400 cells/L and not on antiretroviral therapy in a randomized controlled trial with each arm receiving either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (p=0.029), with Acyclovir reducing overall disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on antiretroviral treatment, particularly among those with high viral loads. In a secondary analysis, we examined the impact of ARV initiation on HSV-2 shedding (among women) and genital ulcer disease (GUD). The rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. Liver disease is a leading cause of mortality among HIV-infected persons. We conducted a study of 500 HIV-infected participants in an HIV care program in rural Rakai, Uganda who were frequency-matched by age, gender and site to 500 HIV-uninfected participants in a population cohort. The prevalence of hepatitis B coinfection in the study population was 5%. The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (P=0.008). HIV infection was associated with a 50% increase in liver fibrosis. Fibrosis was also associated with male gender, herbal medicine use, heavy alcohol consumption, occupational fishing and chronic HBV infection. Among HIV-infected participants, ART reduced fibrosis risk (P=0.030). Elevated sCD14 levels were strongly associated with liver disease in the HIV-positive population in the absence of microbial translocation. These findings suggest that monocytes may have alternative properties associated with liver disease in HIV-infected versus HIV-uninfected Africans. Operational research on how best to improve the quality of HIV care delivered in this setting has also been an important component of our activities. To better understand the impact of peer health workers (PHW) on AIDS care, we conducted a study that demonstrated that task shifting to PHWs positively affected structural and programmatic functions of care delivery by improving clinical organization, medical care access, treatment fatigue, and patient-provider communication, with little evidence for problems with confidentiality and inadvertent disclosure. Qualitative analyses found improvements in patient care and logistics and broad support for the mHealth (mobile phone) intervention among patients, clinic staff, and PHWs.